Process for the preparation of



United States Patent PROCESS FOR THE PREPARATION OF 30:-ACYLOXY-Gfi-HYDROXY-TROPANES Gabor Fodor, Irn W. Viucze, Jzsef Tth, GzaJanzs, and Kornlia Lang, all of Szeged, Hungary, assignors to EgyesultGyogyszer-es Tapszergyar, Budapest, Hun- 8 No Drawing. Application March25, 1958 Serial No. 723,631

Claims priority, application Hungary April 1,1957 8 Claims. (Cl.260-292) This invention is concerned with a process for the prep-.aration of 3a-acyloxy-6B-hydroxy-tropanes. These monoacyl derivativesof tropanes are important intermediate compounds for the preparation of6-tropene-3a-ol and through this compound for the preparation of6,7fi-epoxy- 3a-hydroxy-tropane and 6,7/3-epoxy-3a-acyloXy-tropane.

Up to the present it has not been possible to prepare the3a-acyloxy-6p-hydroxy-tropanes from 3a.6fl-dihydroxy-tropane neither byselective acylation of this compound, nor by the partial deacylation oftheir diacyl derivatives. (Stoll et al., -Helv. Chim. Acta 36, 1506, andfollowing, 1953.)

It has been found that 3u-acyloxy-6p-hydroxy-tropane may be prepared bypartial hydrolysis of the 3a.6,B-diacy1- oxy-tropane with dilute aqueousalkali hyd'roxyde in presence of a watersoluble organic solvent havingno hydroxyl group.

It is a further object of the invention to prepare new racemic3a-isovaleroxy-6p-tropane and 1-3a-tropoyloxy- 6p-hydroxy-tropane.

As hydroxyl-free solvents tetrahydrofurane, dioxane, dimethyl-formamide,but with a special advantage acetone can be used. An optimal yield ofthe mono-acyl compound can be obtained at temperatures between 25 and 30centigrade. One can employ advantageously alkali hydroxide in a quantitybetween an amount calculated for the saponification of one acyl radicaland for the twofold of the same. In this way the3ot-acyloxy-6-hydroXytropane can be obtained with a good yield, alongwith an unchanged diacyl-tropane and smaller amounts of 30:65-dihydroxy-tropane. In this way from the 3a.6 8-diacetoxytropane the3u-acetoxy-6 3-hydroxy-tropane and from the di-isovaleroxy-tropane the3a-isovaleroxy-6/8-hydroxytropane can be obtained. In a similar waydi-l-tropic acid ester of the l-3m6B-dihydroxy-tropane the 1-3a-tropoyl-6B-hydroxy-tropane can be obtained. This last compound has a mydriaticelfect. This partial deacylation could not be expected in view of theprior art.

Example 1 24 g. 3u.6fi-diacetoxytropane are dissolved in 700 ml. acetoneand 1700 ml. n/10 NaOH are added to the solution. This solution isheated for 65 minutes to 30 centigrades, then neutralized with about 120ml. n HCl. The reaction mixture is evaporated to dryness in vacuo, theresidue dissolved in 200 ml. water, its pH adjusted withcalciumcarbonate to 10, and the base extracted six times with 100 ml.chloroform each. The chloroform extraction is dried on sodiumsulphateand the chloroform distilled off in waterbath. In this way a viscous oilis obtained, which becomes crystalline when triturated with ice-cooledether. Yield: 15.6 g. (78%) pure 3ot-acetoxy- 6B-hydroxytropane. M.P.117-118 centigrades. 3.82 g.

2,905,687 Patented Sept. 22, 1959 2 3u.6fi-diacetoxy-tropane can berecovered from the ethereal mother liquor.

Example 2 6.5 g. racemic 3a.6/3-diisovaleroxytropane-hydrobromide isdissolved in a mixture of 710 ml. n/ 10 NaOH and 200 ml. acetone. Thismixture is allowed to stand at room temperature for 6 hours, thenneutralized with diluted HCl and the solvent distilled olf below 50centigrades. The residue is dissolved in 40 ml. water, the mixtureadjusted with calcium carbonate to pH 10 and hereafter extracted tentimes with 50 ml. chloroform each. The combined chloroform extracts aredried over Na SO and the chloroform is driven off. 2.5 g. racemic30:.6B- dihydroxytropane-3-mono-isovalerate is obtained. This compoundcan be dissolved in anhydrous alcohol, and converted with hydrochloricacid into its hydrochloride salt, the M.P. of which is centigrades. Thiscompound is identical with the racemie valeroidine hydrochlorideprepared in a difierent way.

Analysis-Calculated: 0:56.25, H=8.65. C=56.22, H=8.90.

Found Example 3 According to the process described in Example 2 the1-3a-tropoyl-3u.6p-dihydroxytropane (hydrobromid, M.P. 148 centigrades,[a] ---30 in water) can be obtained from the di-l-tropic acid ester ofthe l-3oa6 3dihydroxytropane.

What we claim is:

1. A process for the preparation of a 3a-acy1oxy-6flhydroxy-tropanecomprising partially saponifying a 3:165- di-acyloxy-tropane selectedfrom the group consisting of 3a.6fl-diacetoxy-tropane,3a.66-diisovaleroxy-tropane, and the di-l-tropic acid ester of thel-3a.-6B-dihydroxy-tropane by means of diluted aqueous alkalihydroxidesolution, in presence of a water-soluble organic solvent containing nohydroxy groups selected from the group consisting of tetrahydrofurane,dioxane, dimethyl-formamide, and acetone.

2. A process according to claim 1, in which the quantity of thealkalihydroxide employed for the partial saponification lies between theamount calculated for the saponification of one acyl radical and thetwofold of the same.

3. A process for the preparation of a 3a-acyloxy-6/3- hydroxy-tropaneaccording to claim 1, in which the saponification is effected between 25and 30 Centigrade.

4. A process for the preparation of a 3u-acyloxy-6fihydroxy-tropaneaccording to claim 1, in which acetone is employed as a hydroxyl-freeorganic solvent.

5. A process for the preparation of 3a-acetoxy-6/3- hydroxy-tropane, inwhich the 3u.6,8-diacetoxy-tropane is partially saponified by means ofdiluted aqueous alkali hydroxide solution, in presence of a watersoluble hydroxy-free organic solvent selected from the group consistingof tetrahydrofurane, dioxane, dimethyl-formamide, and acetone.

6. A process for the preparation of 3a-isovaleroxy-6phydroxy-tropane inwhich the 3u.6fl-diisovaleroxy-tropane is partially saponified by meansof diluted aqueous alkali hydroxide solution in presence of a watersoluble hydroxyfree organic solvent selected from the group consistingof tetrahydrofurane, dioxane, dimethyl-formamide, and acetone. 1' gj 7.A process for the preparation of 1-3atropoyloxy-'6B hydroxy-tropane inwhich 1-di-tropoy1-3u.6{3-dihydroxytropane is partially saponified bymeans of diluted aque-

1. A PROCESS FOR THE PREPARATION OF A 3A-ACYLOXY-6BHYDROXY-TROPANECOMPRISING PARTIALLY SAPONIFYING A 3A,6BDI-ACYLOXY-TROPANE SELECTED FROMTHE GROUP CONSISTING OF 3A,6B-DIACETOXY-TROPANE,3A,6B-DIISOVALEROXY-TROPANE, AND THE DI-L-TROPIC ACID ESTER OF THE1-3A,6B-DIHYDROXY-TROPANE BY MEANS OF DILUTED AQUEOUS ALKALIHYDROXIDESOLUTION, IN PRESENCE OF A WATER-SOLUBLE ORGANIC SOLVENT CONTAINING NOHYDROXY GROUPS SELECTED FROM THE GROUP CONSISTING OF TETRAHYDROFURANE,DIXANE, DIMETHYL-FORMAMIDE, AND ACETONE.
 8. THE1-3A-TROPOYLOXY-63-HYDROXY-TROPANE.